Pigmentation disorders can take a variety of forms like hyperpigmentation and hypopigmentation, such as melasma (dark patches experienced in pregnancy), liver spots (which often develop with age), as a side effect of birth control pills, and as a persistent result of acne, burns, bites and other skin injuries, and vitiligo.
In the United States, the most commonly used treatment for hyperpigmentation is 1,4-benzenediol, which is known as hydroquinone. Treatment with hydroquinone interferes with the action of tyrosinase, which is an enzyme used in the synthesis of melanin, and compositions are sold across the counter at about 2% hydroquinone and by prescription at higher concentrations.
Hydroquinone compositions are effective but have some undesirable side effects. These can be burning, redness, sensitization and irritation in some patients.
Additionally, the hydroquinone compositions frequently discolor over time and turn from a whitish color to a brown or even black. Without being limited to the mechanism of this discoloration, it is believed that the discoloration may be caused at least in part by oxidation of the hydroquinone. Discoloration of hydroquinone compositions may be accelerated by repeated exposure to oxygen or exposing the compositions to high temperatures, which may be found inside a car or delivery vehicle on a hot sunny day.
The natural pH for conventional hydroquinone compositions is acidic, generally less than about 4 even though this is harsh to the skin and to other components of the product. This range of pH has been preferred for hydroquinone compositions, because it has been believed that the hydroquinone is less likely to excessively discolor under acid conditions. Variations in pH have proven to result in excessive discoloration ranging from brownish to black. The present invention combats this problem, with hydroquinone compositions in the neutral pH range, preferably a pH of from about 5.5 to about 8.0, more preferably a pH of from about 5.5 to about 7.5, and most preferably at a pH of from about 6.0 to about 7.5.
Some hydroquinone compositions include antioxidants, such as ascorbyl palmitate. Other antioxidants, for example cationic salts of acidic ascorbyl esters, most preferably magnesium ascorbyl phosphate, aminopropyl ascorbyl phosphate, and sodium ascorbyl phosphate, have not been utilized in combination with hydroquinone in view of the acidic pH, generally from about 3.4 to about 3.5, and the recommended pH range for magnesium ascorbyl phosphate is about 7.0 to 8.5. However, hydroquinone discolors at the pH range of 7.0 to 8.5. Thus, while cationic salts of acidic ascorbyl esters, preferably magnesium ascorbyl phosphate and aminopropyl ascorbyl phosphate, have beneficial antioxidant effects on the skin, the combination with hydroquinone in the invention results in a compatible and stable composition.
Antioxidants, preferably sulfites, including but not limited to sulfites, bisulfites, metabisulfites, their salts, and their derivatives, most preferably sodium metabisulfite, have been used to stabilize certain compositions, which have included hydroquinone. Since hydroquinone has a tendency to discolor through oxidation, these antioxidants are used because they have greater tendencies to oxidize than hydroquinone. Sodium metabisulfite has the added advantage that it does not discolor by oxidation. In hydroquinone and sodium metabisulfite compositions, it is believed that the sodium metabisulfite oxidizes first and delays the start of any oxidation of the hydroquinone, so that excessive discoloration is delayed or totally avoided. However, these hydroquinone-containing compositions were in the acidic pH range and did not contain cationic salts of acidic ascorbyl esters, such as magnesium ascorbyl phosphate.
While patients suffer from pigmentation disorders, they may also suffer from other skin disorders and signs of aging, including but not limited to rough skin texture, mottled pigmentation, sallow complexion, lines and wrinkles. Retinoid compositions, in particular retinoic acid, retinal, and their derivatives, isomers and analogs (such as adapalene, tazarotene and isotretoin) are known to be effective in improving rough skin texture, mottled pigmentation, sallow complexion, lines and wrinkles.
It would be desirable to combine the pigmentation disorder treatment with this skin benefit ingredient in one composition. However, a problem with a formulation containing both retinoids and hydroquinone has been their incompatible pH ranges. Thus, merely adding one retinoid to a hydroquinone composition would result in instability and/or discoloration, and adding hydroquinone to a retinoid product would have a similar result.